Cyclacel Ltd., 1 James Lindsay Place, Dundee DD1 5JJ, Scotland, UK.
J Med Chem. 2010 Jun 10;53(11):4367-78. doi: 10.1021/jm901913s.
Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K(i) values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.
通过对我们的激酶定向化合物库进行基于细胞的筛选，我们发现，一组 N-苯基-4-(噻唑-5-基)嘧啶-2-胺类化合物对癌细胞系具有很强的细胞毒性，能抑制有丝分裂组蛋白 H3 的磷酸化，并导致有丝分裂异常表型。随后证实，这些化合物实际上是 Aurora A 和 B 激酶的有效抑制剂。结果表明，Aurora 激酶抑制的效力和选择性与这些化合物中苯胺对位取代基的存在有关。先导化合物 4-甲基-5-(2-(4-吗啉基苯基氨基)嘧啶-4-基)噻唑-2-胺（18；对 Aurora A 和 B 的 K(i) 值分别为 8.0 和 9.2 nM）的抗癌作用源自有丝分裂失败后细胞死亡，并由于 Aurora A 和 B 激酶的细胞抑制而导致多倍体增加。初步的体内评估表明，化合物 18 具有口服生物利用度，并具有抗癌活性。化合物 18（CYC116）目前正在癌症患者中进行 I 期临床评估。
